Benzimidazole Derivatives

ABSTRACT

Novel compounds of the formula I (I), in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R, Q, W, X and Z have the meanings indicated in Patent Claim  1 , are suitable as antidiabetics.

The invention relates to compounds of the formula I

in which

-   R¹, R², R³, R⁴ each, independently of one another, denote H, A or    Hal,-   R⁵, R⁶, R⁷, R⁸ each, independently of one another, denote H, A, Hal,    OH or OA,    -   where R⁸ is absent if Q=N,-   R⁹, R¹⁰, R¹¹-   R¹², R¹³ each, independently of one another, denote H, A or Hal,    where one of the radicals R⁹, R¹⁰, R¹¹, R¹² or    -   R¹³ is ≠H,-   R denotes CO—NR¹⁸R¹⁹ or Het,-   Q denotes N or C,-   X denotes O or NR¹⁴R¹⁵,-   W denotes (CR¹⁴R¹⁵)_(m), CO, NR¹⁴R¹⁵, S(O)_(n) or is absent,-   Z denotes (CR²⁰R²¹)_(m),-   R¹⁴, R¹⁵ each, independently of one another, denote H or A,-   R¹⁶, R¹⁷ each, independently of one another, denote H or A,-   R¹⁸, R¹⁹ each, independently of one another, denote H or A,-   R²⁰ denotes H or A,-   R²¹ denotes H, A or CH₂OH,-   R¹⁸ and R²¹ together also denote (CR¹⁶R¹⁷)_(p,)-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA,    NR¹⁴R¹⁵ and/or ═O (carbonyl oxygen),-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7H atoms may be replaced by F,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1, 2, 3 or 4,-   n denotes 0, 1 or 2,-   p denotes 1, 2 or 3,    and pharmaceutically usable derivatives, solvates, salts and    stereoisomers thereof, including mixtures thereof in all ratios.

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

It has been found that the compounds of the formula I and salts thereofhave very valuable pharmacological properties while being welltolerated. They exhibit SGLT1- and SGLT2-(sodium dependent glucoseco-transporter) inhibiting properties and can therefore be employed forcombating and preventing type 1 and type 2 diabetes.

The absorption of glucose in the brush border of the small intestine andthe proximal tubules of the kidney against a concentration gradientoccurs via epithelial sodium-dependent glucose cotransporters (SGLTs).At least two major classes of SGLTs have been described: SGLT1 (forexample Lee W. S. et al. (1994) The high-affinity Na⁺/Glucoseco-transporter: reevaluation of function and distribution of expression.J. Biol. Chem. 269, 12032-12039) and SGLT2 (for example Mackenzie B. etal. (1994) SAAT1 ist a low-affinity Na⁺/glucose cotransporter and not anamino acid transporter. J. Biol. Chem. 269, 22488-22491).

SGLT1 is thought to be important for the absorption of glucose in thegut, whereas SGLT2 is probably primarily responsible for there-absorption of freely filtered glucose in the kidney.

The major change in diabetes mellitus is hyperglycaemia. This is notonly a symptom of the disease, but also a potential pathogenic factorleading to multiple chronic diabetic micro- and macrovascularcomplications and an impairment of insulin secretion and sensitivity(Klein R. (1995), Hyperglycemia and microvascular and macrovasculardisease in diabetes, Diabetes Care 18, 258-268; Rossetti L. (1995),Glucose toxicity: the implications of hyperglycemia in thepathophysiology of diabetes mellitus, Clin. Invest. Med. 18, 255-260).Thus, an important therapeutic aim in the case of the diabetes patientis exclusive regulation of the blood glucose levels within the normalrange. In accordance with their described function, inhibition of SGLTsresults in reduced absorption and increased excretion of glucose, and asubsequent decrease in blood glucose levels. Thus, suppression of SGLTsmay be a suitable alternative for the treatment of diabetes.

The literature describes a number of classes of substance having an SGLTaction. The model for all these structures was the natural productphlorizin. Aromatic glycoside derivatives are known from WO 2004/052902and WO 2004/052903. Propiophenone glycosides are described in WO0280936, WO 0280935, JP 2000080041 and EP 850948.Glucopyranoslyoxybenzylbenzenes are described in WO 0244192, WO 0228872and WO 0168660. Glucopyranosyloxypyrazoles are known from WO 0268440, WO0268439, WO 0236602 and WO 0116147. O-glycoside benzamides are disclosedin WO 0174835 and WO 0174834. C-arylglycosides are described in WO0127128 and US 2002137903. All known structures contain the glucose as avery important structural element. Furthermore, US 2002/132807 disclosesdiaryl sulfide compounds for the treatment of inflammatory and immunediseases. EP 0 953 357 A1 describes in general glycoside compounds asrenal drug carriers, and WO 95/23780 describes4-hydroxyphenoxyheterocycloalkyl compounds as skin lighteners.

Other indolizine derivatives are known from WO 2004/108722 and fromBioorg. Med. Chem. Lett. 2006, 16, 3998ff.

The compounds according to the invention have high splitting withrespect to the desired affinity from SGLT₂ to SGLT₁.

The compounds of the formula I are distinguished by favourable actionson glucose metabolism, in particular they lower the blood sugar leveland are suitable for the treatment of type 1 and type 2 diabetes. Thecompounds can therefore be employed alone or in combination with furtherblood sugar-lowering active ingredients (antidiabetics).

The compounds of the formula I are furthermore suitable for theprevention and treatment of late damage in diabetes, such as, forexample, nephropathy, retinopathy, neuropathy and syndrome X, obesity,cardiac infarction, myocardial infarction, peripheral arterial occlusiondiseases, thromboses, arteriosclerosis, inflammation, immune diseases,autoimmune diseases, such as, for example, AIDS, asthma, osteoporosis,cancer, psoriasis, Alzheimer's, schizophrenia and infectious diseases,preferably the treatment of type 1 and type 2 diabetes and for theprevention and treatment 15 of late damage in diabetes, syndrome X andobesity.

The compounds of the formula I can be employed as medicament activeingredients in human and veterinary medicine, in particular for thetreatment and prevention of type 1 and type 2 diabetes.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, characterised in that

a) a compound of the formula II

in whichR¹, R², R³, R⁴, R⁹, R¹⁰, R¹¹, R¹², R¹³ and W have the meanings indicatedin Claim 1,is reacted with a compound of the formula III

in whichR⁵, R⁶, R⁷, R⁸, R, Q, W and Z have the meanings indicated in Claim 1,orb) a compound of the formula IV

in whichR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, Q and W have themeanings indicated in Patent Claim 1,is reacted with a compound of the formula V

L-Z-R  V

in which Z and R have the meanings indicated in Patent Claim 1, andL denotes Cl, Br, I or a free or reactively functionally modified OHgroup,and/ora base or acid of the formula I is converted into one of its salts.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term “solvates of thecompounds” is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force. Solvateare, for example, mono- or dihydrates or alcoholates.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds.

The term “prodrug derivatives” is taken to mean compounds of the formulaI which have been modified with, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the active compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.These are particularly preferably mixtures of stereoisomeric compounds.

The compounds according to the invention may also be in variouspolymorphic forms, for example as amorphous and crystalline polymorphicforms. All polymorphic forms of the compounds according to the inventionbelong within the scope of the invention and are a further aspect of theinvention.

For all radicals which occur more than once, their meanings areindependent of one another.

Above and below, the radicals or parameters R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁸, R¹⁹, Q, R, W, X and Z have the meaningsindicated under the formula I, unless expressly indicated otherwise.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

R¹, R², R³, R⁴ preferably denote, in each case independently of oneanother, H, CH₃, F or Cl.

R⁵, R⁶, R⁷, R⁸ preferably denote, in each case independently of oneanother, H, CH₃, Hal or OCH₃,

where R⁸ is absent if Q=N.

R⁹, R¹⁰, R¹¹, R¹², R¹³ preferably denote, in each case independently ofone another, H, CH₃, F or Cl, where one of the radicals R⁹, R¹⁰, R¹¹,R¹² or R¹³ is ≠H.

R⁹, R¹³ particularly preferably denote, in each case independently ofone another, CH₃, F or Cl.

R¹¹ particularly preferably denotes H or CH₃,

R¹⁰, R¹² particularly preferably denote H.

X preferably denotes O.

W preferably denotes (CR¹⁴R¹⁵)_(m) or CO.

Q preferably denotes C.

R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ preferably denote H.

R²⁰ preferably denotes H.

R²¹ preferably denotes H or CH₂OH.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl,2,1,3-benzoxadiazol-5-yl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.Irrespective of further substitutions, Het may thus also denote, forexample, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes a mono- or bicyclic saturated, unsaturated oraromatic heterocycle having 1 to 4 N, O and/or S atoms, which may bemono- or disubstituted by NR¹⁴R¹⁵ and/or ═O (carbonyl oxygen).

Het particularly preferably denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,benzo-1,3-dioxolyl, indazolyl or benzo-2,1,3-thiadiazolyl, each of whichis unsubstituted or mono- or disubstituted by NR¹⁴R¹⁵ and/or ═O(carbonyl oxygen).

Hal preferably denotes F, Cl or Br, but also 1.

m preferably denotes 0, 1 or 2.

n preferably denotes 1 or 2.

The compounds of the formula I can have one or more chiral centres andtherefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to In, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated under the formula I, but in which

-   in Ia A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5 or    6 C atoms, in which 1-5H atoms may be replaced by F;-   in Ib R¹, R², R³, R⁴ each, independently of one another, denote H,    CH₃, F or Cl;-   in Ic R⁵, R⁶, R⁷, R⁸ each, independently of one another, denote H,    CH₃, Hal or OCH₃,    -   where R⁸ is absent if Q=N;-   in Id R⁹, R¹⁰, R¹¹,    -   R¹², R¹³ each, independently of one another, denote H, CH₃, F or        Cl,    -   where one of the radicals R⁹, R¹⁰, R¹¹, R¹² or R¹³ is ≠H;-   in Ie R⁹, R¹³ each, independently of one another, denote CH₃, F or    Cl,    -   R¹¹ denotes H or CH₃,    -   R¹⁰, R¹² denote H;-   in If X denotes O;-   in Ig W denotes (CR¹⁴R¹⁵)_(m) or CO;-   in Ih R¹⁴, R¹⁵ denote H;-   in Ii R¹⁶, R¹⁷ denote H;-   in Ij R¹⁸, R¹⁹ denote H;-   in Ik R²⁰ denotes H,    -   R²¹ denotes H or CH₂OH;-   in Il Het denotes a mono- or bicyclic saturated, unsaturated or    aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be    mono- or disubstituted by NR¹⁴R¹⁵ and/or ═O (carbonyl oxygen);-   in Im Het denotes piperidinyl, piperazinyl, pyrrolidinyl,    morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl,    triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl,    pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,    benzo-1,3-dioxolyl, indazolyl or benzo-2,1,3-thiadiazolyl, each of    which is unsubstituted or mono- or disubstituted by NR¹⁴R¹⁵ and/or    ═O (carbonyl oxygen);-   in In A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5 or    6 C atoms, in which 1-5H atoms may be replaced by F,    -   Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,        furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl,        triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl,        pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,        benzo-1,3-dioxolyl, indazolyl or benzo-2,1,3-thiadiazolyl, each        of which is unsubstituted or mono- or disubstituted by NR¹⁴R¹⁵        and/or ═O (carbonyl oxygen),    -   R¹, R², R³, R⁴ each, independently of one another, denote H,        CH₃, F or Cl,    -   R⁵, R⁶, R⁷, R⁸ each, independently of one another, denote H,        CH₃, Hal or OCH₃,        -   where R⁸ is absent if Q=N,    -   R⁹, R¹³ each, independently of one another, denote CH₃, F or Cl,    -   R denotes CO—NR¹⁸R¹⁹ or Het,    -   R¹¹ denotes H or CH₃,    -   R¹⁰, R¹² denote H,    -   Q denotes N or C,    -   X denotes 0,    -   W denotes (CR¹⁴R¹⁵)_(m) or CO,    -   Z denotes (CR²⁰R²¹)_(m),    -   R¹⁴, R¹⁵ denote H,    -   R¹⁶, R¹⁷ denote H,    -   R¹⁸, R¹⁹ denote H,    -   R²⁰ denotes H,    -   R²¹ denotes H or CH₂OH,    -   R¹⁸ and R²¹ together also denote (CR¹⁶R¹⁷)_(p),    -   m denotes 0, 1 or 2,    -   p denotes 1 or 2,        and pharmaceutically usable derivatives, solvates, salts and        stereoisomers thereof, including mixtures thereof in all ratios.

In addition, the compounds of the formula I and also the startingmaterials for their preparation are prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use may also be made here of variants known per se which are notmentioned here in greater detail.

If desired, the starting materials can also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds of the formula I.

The starting compounds of the formulae II, III and IV are generallyknown. If they are novel, however, they can be prepared by methods knownper se.

Compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

The reaction is generally carried out in an inert solvent, in thepresence of a suitable oxidant, such as, for example, sodium disulfiteor oxygen.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about 0° and150°, normally between 30° and 140°, particularly preferably between 60°and 120° C.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents; N-methylpyrrolidone (NMP) is particularlypreferred.

Compounds of the formula I can furthermore preferably be obtained byreacting compounds of the formula IV with compounds of the formula V.

The reaction is generally carried out in an inert solvent, in thepresence of an acid-binding agent, preferably an alkali oralkaline-earth metal hydroxide, carbonate or bicarbonate or another saltof a weak acid of the alkali or alkaline-earth metals, preferably ofpotassium, sodium, calcium or caesium. The addition of an organic base,such as triethylamine, dimethylaniline, pyridine or quinoline, or of anexcess of the phenol component of the formula IV or of the alkylationderivative of the formula V may also be favourable. Depending on theconditions used, the reaction time is between a few minutes and 14 days,the reaction temperature is between about 0° and 150°, normally between10° and 130°, particularly preferably between 20 and 80°.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Acetonitrile is particularly preferred.

In the compounds of the formula V, L preferably denotes Cl, Br, I or afree or reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy). Lparticularly preferably denotes Br.

Pharmaceutical Salts and Other Forms

The said compounds of the formula I can be used in their final non-saltform. On the other hand, the present invention also encompasses the useof these compounds in the form of their pharmaceutically acceptablesalts, which can be derived from various organic and inorganic acids andbases by procedures known in the art. Pharmaceutically acceptable saltforms of the compounds of the formula I are for the most part preparedby conventional methods. If the compound of the formula I contains acarboxyl group, one of its suitable salts can be formed by reacting thecompound with a suitable base to give the corresponding base-additionsalt. Such bases are, for example, alkali metal hydroxides, includingpotassium hydroxide, sodium hydroxide and lithium hydroxide; alkalineearth metal hydroxides, such as barium hydroxide and calcium hydroxide;alkali metal alkoxides, for example potassium ethoxide and sodiumpropoxide; and various organic bases, such as piperidine, diethanolamineand N-methylglutamine. The aluminium salts of the compounds of theformula I are likewise included. In the case of certain compounds of theformula I, acid-addition salts can be formed by treating these compoundswith pharmaceutically acceptable organic and inorganic acids, forexample hydrogen halides, such as hydrogen chloride, hydrogen bromide orhydrogen iodide, other mineral acids and corresponding salts thereof,such as sulfate, nitrate or phosphate and the like, and alkyl- andmonoarylsulfonates, such as ethanesulfonate, toluenesulfonate andbenzenesulfonate, and other organic acids and corresponding saltsthereof, such as acetate, trifluoroacetate, tartrate, maleate,succinate, citrate, benzoate, salicylate, ascorbate and the like.Accordingly, pharmaceutically acceptable acid-addition salts of thecompounds of the formula I include the following: acetate, adipate,alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate,caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate,digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate,glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide,isethionate, isobutyrate, lactate, lactobionate, malate, maleate,malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate,monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate,3-phenylpropionate, phosphate, phosphonate, phthalate, but this does notrepresent a restriction.

Furthermore, the base salts of the compounds of the formula I includealuminium, ammonium, calcium, copper, iron(III), iron(II), lithium,magnesium, manganese(III), manganese(II), potassium, sodium and zincsalts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyaminoresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the formula I of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compounds ofthe formula I can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds of the formula I areprepared by bringing the free acid form into contact with a sufficientamount of the desired base, causing the formation of the salt in aconventional manner. The free acid can be regenerated by bringing thesalt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound of the formula I contains more than one group which iscapable of forming pharmaceutically acceptable salts of this type, theformula I also encompasses multiple salts. Typical multiple salt formsinclude, for example, bitartrate, diacetate, difumarate, dimeglumine,diphosphate, disodium and trihydrochloride, but this is not intended torepresent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Owing to their molecular structure, compounds of the formula I accordingto the invention can be chiral and can accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament (pharmaceutical composition), in particularby non-chemical methods. In this case, they can be converted into asuitable dosage form together with at least one solid, liquid and/orsemi-liquid excipient or adjuvant and optionally in combination with oneor more further active ingredients.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates, salts and stereoisomers thereof, including mixtures thereof inall ratios, and optionally excipients and/or adjuvants.

These compositions can be used as medicaments in human or veterinarymedicine.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the disease conditiontreated, the method of administration and the age, weight and conditionof the patient, or pharmaceutical formulations can be administered inthe form of dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The active ingredients can also becombined with a free-flowing inert excipient and then pressed directlyto give tablets without carrying out the granulation or dry-pressingsteps. A transparent or opaque protective layer consisting of a shellacsealing layer, a layer of sugar or polymer material and a gloss layer ofwax may be present. Dyes can be added to these coatings in order to beable to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa prespecified amount of the compounds. Syrups can be prepared bydissolving the compounds in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compounds in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts, solvates and physiologicallyfunctional derivatives thereof and the other active ingredients can alsobe administered in the form of liposome delivery systems, such as, forexample, small unilamellar vesicles, large unilamellar vesicles andmultilamellar vesicles. Liposomes can be formed from variousphospholipids, such as, for example, cholesterol, stearylamine orphosphatidylcholines.

The compounds of the formula I and the salts, solvates andphysiologically functional derivatives thereof and the other activeingredients can also be delivered using monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Thecompounds can also be coupled to soluble polymers as targeted medicamentcarriers. Such polymers may encompass polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidophenol,polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,substituted by palmitoyl radicals. The compounds may furthermore becoupled to a class of biodegradable polymers which are suitable forachieving controlled release of a medicament, for example polylacticacid, poly-epsilon-caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in the freeze-dried (lyophilised) state,so that only the addition of the sterile carrier liquid, for examplewater for injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula I and ofthe other active ingredient depends on a number of factors, including,for example, the age and weight of the animal, the precise diseasecondition which requires treatment, and its severity, the nature of theformulation and the method of administration, and is ultimatelydetermined by the treating doctor or vet. However, an effective amountof a compound is generally in the range from 0.1 to 100 mg/kg of bodyweight of the recipient (mammal) per day and particularly typically inthe range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as an individual doseper day or more usually in a series of part-doses (such as, for example,two, three, four, five or six) per day, so that the total daily dose isthe same. An effective amount of a salt or solvate or of aphysiologically functional derivative thereof can be determined as thefraction of the effective amount of the compound per se.

The invention furthermore relates to the use of compounds of the formulaI, in combination with at least one further medicament activeingredient, preferably for the treatment of type 1 and type 2 diabetes,in particular for lowering blood sugar.

Suitable further active ingredients for the combination preparationsare:

All antidiabetics mentioned in the Rote Liste [Red List] 2001, Chapter12.

They can be combined with the compounds of the formula I according tothe invention, in particular in order to enhance the actionsynergistically. The active-ingredient combination can be administeredeither by administration of the active ingredients to the patientseparately or in the form of combination preparations which comprise aplurality of active ingredients in a single pharmaceutical composition.Most of the active ingredients listed below are disclosed in USPDictionary of USAN and International Drug Names, US Pharmacopeia,Rockville 2001. Antidiabetics include insulin and insulin derivatives,such as, for example, Lantus® (see www.lantus.com) or HMR 1964,fast-acting insulins (see U.S. Pat. No. 6,221,633), GLP-1 derivatives,such as, for example, those disclosed by Novo Nordisk A/S in WO98/08871, and orally effective hypoglycaemic active ingredients.

The orally effective hypoglycaemic active ingredients preferably includesulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1agonists, potassium channel openers, such as, for example, thosedisclosed by Novo Nordisk A/S in WO 97/26265 and WO 99/03861, insulinsensitisers, inhibitors of liver enzymes which are involved in thestimulation of gluconeogenesis and/or glycogenolysis, glucose uptakemodulators, compounds which modify fat metabolism, such asantihyperlipidaemic active ingredients and antilipidaemic activeingredients, compounds which reduce the intake of foods, PPAR and PXRagonists, and active ingredients which act on the ATP-dependentpotassium channel of the beta cells.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with an HMGCoA reductase inhibitor, such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with a cholesterol absorption inhibitor,such as, for example, ezetimibe, tiqueside, pamaqueside.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with a PPAR gamma agonist, such as, forexample, rosiglitazone, pioglitazone, JTT-501, GI 262570.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with PPAR alpha agonist, such as, forexample, GW 9578, GW 7647.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with a mixed PPAR alpha/gamma agonist, suchas, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, AVE 0897, or asdescribed in WO 00/64888, WO 00/64876, WO 03/20269.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate, such as, for example,fenofibrate, clofibrate, bezafibrate.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with an MTP inhibitor, such as, for example,implitapide, BMS-201038, R-103757. In an embodiment of the invention,the compounds of the formula I are administered in combination with bileacid absorption inhibitor (see, for example, U.S. Pat. No. 6,245,744 orU.S. Pat. No. 6,221,897), such as, for example, HMR 1741.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, such as, for example,JTT-705.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorber, suchas, for example, cholestyramine, colesevelam.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), such as, for example, HMR1171, HMR1586.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with an ACAT inhibitor, such as, forexample, avasimibe.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with an antioxidant, such as, for example,OPC-14117.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor, suchas, for example, NO-1886.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with an ATP citrate lyase inhibitor, suchas, for example, SB-204990.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with a squalene synthetase inhibitor, suchas, for example, BMS-188494. In an embodiment of the invention, thecompounds of the formula I are administered in combination with alipoprotein(a) antagonist, such as, for example, CI-1027 or nicotinicacid. In an embodiment of the invention, the compounds of the formula Iare administered in combination with a lipase inhibitor, such as, forexample, orlistat.

In an embodiment of the invention, the compounds of the formula I areadministered in combination with insulin.

In an embodiment, the compounds of the formula I are administered incombination with a sulfonylurea, such as, for example, tolbutamide,glibenclamide, glipizide or glimepiride.

In an embodiment, the compounds of the formula I are administered incombination with a biguanide, such as, for example, metformin.

In another embodiment, the compounds of the formula I are administeredin combination with a meglitinide, such as, for example, repaglinide.

In an embodiment, the compounds of the formula I are administered incombination with a thiazolidinedione, such as, for example,troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compoundswhich are disclosed by Dr. Reddy's Research Foundation in WO 97/41097,in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In an embodiment, the compounds of the formula I are administered incombination with an α-glucosidase inhibitor, such as, for example,miglitol or acarbose.

In an embodiment, the compounds of the formula I are administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide.

In an embodiment, the compounds of the formula I are administered incombination with more than one of the above-mentioned compounds, forexample in combination with a sulfonylurea and metformin, a sulfonylureaand acarbose, repaglinide and metformin, insulin and a sulfonylurea,insulin and metformin, insulin and troglitazone, insulin and lovastatin,etc.

In a further embodiment, the compounds of the formula I are administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A, et al., M.: Hormone and Metabolic Research (2001),33(9), 554-558), NPY antagonists, for example naphthalene-1-sulfonicacid {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}-amide;hydrochloride (CGP 71683A)), MC4 agonists (for example1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amide;(WO 01/91752)), orexin antagonists (for example1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochlorides(SB-334867-A)), H3 agonists(3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (forexample[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (for example urocortin), urocortinagonists, β3 agonists (for example1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol;hydrochlorides (WO 01/83451)), MSH (melanocyte-stimulating hormone)agonists, CCK-A agonists (for example{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525)); serotonin reuptakeinhibitors (for example dexfenfluramines), mixed serotonin compounds andnoradrenergic compounds (for example WO 10 00/71549), 5HT agonists, forexample 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO01/09111), bombesin agonists, galanin antagonists, growth hormone (forexample human growth hormone), growth hormone-releasing compounds(tert-butyl6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(WO 01/85695)), TRH agonists (see, for example, EP 0 462 884) uncouplingprotein 2- or 3-modulators, leptin agonists (see, for example, Lee,Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso,Patricia. Leptin agonists as a potential approach to the treatment ofobesity, Drugs of the Future (2001), 26(9), 873-881), DA agonists(bromocriptine, doprexin), lipase/amylase inhibitors (for example WO00/40569), PPAR modulators (for example WO 00/78312), RXR modulators orTR-β agonists.

In an embodiment of the invention, the additional active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In an embodiment, the additional active ingredient is dexamphatamine oramphetamine.

In an embodiment, the additional active ingredient is fenfluramine ordexfenfluramine.

In yet another embodiment, the additional active ingredient issibutramine.

In an embodiment, the additional active ingredient is orlistat.

In an embodiment, the additional active ingredient is mazindol orphentermine.

In an embodiment, the compounds of the formula I are administered incombination with roughage, preferably insoluble roughage (see, forexample, Carob/Caromax® (Zunft H J; et al., Carob pulp preparation fortreatment of hypercholesterolemia, ADVANCES IN THERAPY (2001September-October), 18(5), 230-6.) Caromax is a carob-containing productfrom Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Höchst, 65926 Frankfurt/Main)). The combination withCaromax® can be effected in a single composition or by administration ofcompounds of the formula I and Caromax® separately. In this connection,Caromax® can also be administered in the form of foods, such as, forexample, in bakery products or muesli bars.

It goes without saying that each suitable combination of the compoundsaccording to the invention with one or more of the above-mentionedcompounds and optionally one or more further pharmacologically activesubstances is regarded as falling within the scope of protection of thepresent invention.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable derivatives, solvates, salts and    stereoisomers thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

The compounds can be tested for their SGLT inhibition properties bymeans of BHK cells expressing SGLT1 and SGLT2. The production of thecells and the testing can be carried out as described below.

Construction and Expression of SGLT1 in BHK Cells

To construct the SGLT1 expression vector (KL225), the SLC5A1 gene(homologous to NM_(—)000343) was amplified from a cDNA library usingstandard PCR technology and cloned over NheI/XhoI sites into thepcDNA3.1 expression vector (Invitrogen) containing neomycin as aselection marker. In this vector, transcription uses theenhancer/promoter of human cytomegalovirus.

The final vector KL225 together with an additional vector containing adihydrofolate reductase gene as a selection marker was introduced intocells. Transfection into BHK21 cells (ATCC CCL-10), cultivated in DMEMmedium (GIBCO/BRL), supplemented with 10% foetal calf serum (FCS) and 20mM glutamine, was carried out using calcium phosphate transfectionsaccording to Graham, F. L. and van der Ebb, A. J. (1973), Virology 52:456 with 5-20 μg of uncut plasmids for 10⁷ cells. Stable transfectantswere selected in medium containing 1 mg/ml of G418 (GIBCO/BRL) and20-5000 nM methotrexate as final concentration, where only cells whichexpressed the neomycin gene and overexpressed the dhfr gene were able togrow. After growth for 2-3 weeks, the cells were cloned (0.5 cells/well)and the clones were investigated for SGLT expression in radioactivityuptake tests.

Construction and Expression of SGLT2 in BHK Cells

To construct the SGLT2 expression vector (KL224), the SLC5A2 gene(homologous to NM_(—)003041) was amplified from a cDNA library usingstandard PCR technology and cloned over NheI/XhoI sites into PCI-neoexpression vector (Promega) containing neomycin as a selection marker.In this vector, transcription uses the enhancer/promoter of humancytomegalovirus and the SV40 polyadenylation signal.

The final vector KL224 together with an additional vector containing adihydrofolate reductase gene as a selection marker was introduced intocells. Transfection into BHK21 cells (ATCC CCL-10), cultivated in DMEMmedium (GIBCO/BRL), supplemented with 10% foetal calf serum (FCS) and 20mM glutamine, was carried out using calcium phosphate transfectionsaccording to Graham, F. L. and van der Ebb, A. J. (1973), Virology 52:456 with 5-20 μg of uncut plasmids for 10⁷ cells. Stable transfectantswere selected in medium containing 1 mg/ml of G418 (GIBCO/BRL) and20-5000 nM methotrexate as final concentration, where only cells whichexpressed the neomycin gene and overexpressed the dhfr gene were able togrow. After growth for 2-3 weeks, the cells were cloned (0.5 cells/well)and the clones were investigated for SGLT expression in radioactivityuptake tests.

Method of SGLT1/2 Activity Measurement

The uptake of ¹⁴C-α-methyl-D-glucopyranoside (AMG) in, for example,Xenopus oocytes injected with the corresponding cRNA has been describedin principle (for example Wen-Sen Lee et al. (1994), J. Biol. Chem. 269,12032-12039; Guofeng You et al. (1995), J. Biol. Chem. 270,29365-29371).

A 96-well cell-based assay was developed and adapted to HTSrequirements:

BHK cells (transfected with SGLT1 or SGLT2) were seeded into 96-wellmicrotitre plates (Cultureplates, Perkin Elmer). After at least 24 h,medium was removed, and the cell layer was washed with assay buffer (140mM NaCl, 2 mM KCl, 1 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 5 mM Tris,adjusted to pH 7.4 using 1 M KOH). After addition of 40 μl of assaybuffer, 50 μl of AMG (50 μM for SGLT1 and 2 mM for SGLT2) in thepresence or absence of compounds, the cells were incubated in a totalvolume of 100 μl at 37° C. for 90 min. Supernatant was removed bysuction and discarded. Cells were washed and lysed by addition of 50 μlof water. After 10 min at room temperature, 200 μl of Micrsoscint 40(Perkin Elmer) were added. The radioactivity was counted in a Topcountmicroplate scintillation counter (Perkin Elmer). The non-specific uptakewas determined in sodium-free assay buffer (266 mM sucrose, 2 mM KCl, 1mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 5 mM Tris, adjusted to pH 7.4 using 1M KOH).

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺FAB (fast atom bombardment) (M+H)⁺ESI (electrospray ionisation) (M+H)⁺ (unless indicated otherwise)

LC-MS and HPLC Conditions

The M+H+ data indicated in the following examples are the measurementresults from the LC-MS measurements:

Hewlett Packard HP 1100 series system having the following features: ionsource: electrospray (positive mode); scan: 100-1000 m/e; fragmentationvoltage: 60 V; gas temperature: 300° C., DAD: 220 nm.

Flow rate: 2.4 ml/min. The splitter used reduced the flow rate for MSafter the DAD to 0.75 ml/min.

Column: Chromolith SpeedROD RP-18e 50-4.6

Solvent: LiChrosolv grade from Merck KGaA

Solvent A: H2O (0.01% of TFA) Solvent B: ACN (0.008% of TFA)

The retention times Rt [min] indicated in the following examples are themeasurement results from the LC-MS measurements.

EXAMPLE 1

The preparation of2-{2-[1-(2,6-dimethylbenzyl)-6-fluoro-1H-benzimidazol-2-yl]-5-methoxy-3-methylphenoxy}acetamide(“A1”) is carried out analogously to the following scheme:

1.1 2,6-Dimethylbenzonitrile (“1”) is dissolved in methanol/NH₃ (w=10%)and hydrogenated for 16 hours at 5 bar and 50° C. over Raney nickel andhydrogen. The reaction solution is filtered through Celite, and thesolvent is removed in vacuo, giving the product “2” in quantitativeyield as oil; LC-MS: 1.307 min, m/e 136.5 (M+H⁺).

1.2 2,4-Difluoro-1-nitrobenzene (“3”, 1 eq) is dissolved in DMF, and asolution of “2” (1 eq) in DMF is added. After addition ofN-ethyldiisopropylamine (1 eq), the reaction is heated at 85° C. for 18hours. After cooling, the solvent is removed in vacuo, the residue istaken up in diethyl ether and washed three times with water. The organicphase is dried over sodium sulfate, and the solvent is removed in vacuo,giving the crude product “4” in a yield of 64%, which is employed in thenext step without further purification; LC-MS: 2.496 min; m/e 275.15(M+H⁺); 297.15 (M+Na⁺).

1.3 Nitroamine “4” (1 eq) is suspended in glacial acetic acid, and zinc(coarsely powdered, 5.9 eq) is added. The suspension is heated underreflux for 3 hours within 30 min. After cooling to room temperature, themixture is diluted with water and adjusted to pH 14 using aqueous NaOH(32%) and extracted four times with dichloromethane. The combinedorganic extracts are washed twice with saturated NaCl solution, driedover sodium sulfate, and the solvent is removed in vacuo. The crudeproduct is purified by column chromatography on normal-phase silica gel,giving the product “5” as powder in a yield of 39%; LC-MS 1.591 min, m/e245.15 (M+H⁺).

1.4 DMF (5 eq) is cooled to <10° C., and phosphoryl chloride (1.3 eq) iscarefully added dropwise. 3,5-Dihydroxytoluene (1 eq) in DMF (3.4 eq) issubsequently carefully added dropwise at <10° C. and warmed to roomtemperature overnight. The suspension is cooled, and ice is added. Themixture is subsequently adjusted to pH 9-14 using concentrated NaOH andheated to 90° C. During this operation, the pH is constantly re-adjustedto pH 9-14 using conc. NaOH until the pH has stabilised. The mixture issubsequently cooled to 10° C. and adjusted to pH 1-3 using concentratedhydrochloric acid. The suspension is cooled overnight, filtered withsuction and washed with ice-water. The crystals are dried in vacuo,giving the product “7” as orange-yellow powder in a yield of 63%; m.p.181-183°; LC-MS: 0.974 min, m/e: 153.1 (M+H⁺).

1.5 Aldehyde “7” (1 eq) is dissolved in acetone, iodomethane (1.2 eq)and potassium carbonate (2.2 eq) are added, and the mixture is boiledunder reflux for 5 hours. The solvent is removed in vacuo, and theproduct is purified by column chromatography on normal-phase silica gel,giving the product “8” in a yield of 68%; LC-MS: 1.538 min, m/e 167.1(MH⁺).

1.6 Aldehyde “8” (1 eq) is dissolved in acetonitrile, potassiumcarbonate (3 eq) and 2-iodoacetamide (1.2 eq) are added. The solution isheated to reflux over the course of 20 minutes, and stirring iscontinued for 4 hours. After filtration, the substance crystallises outover the course of 2 days. The crystals are filtered off, washed withacetonitrile and dried at 40° C. in vacuo, giving the product “9” in ayield of 74%; m.p. 173-174°; LC-MS: 0.975 min; m/e 224.15 (M+H⁺), 246.15(M+Na⁺).

1.7 Diamine “5” (1 eq) and aldehyde “9” (1.1 eq) are dissolved in NMP,and sodium disulfite (1.1 eq) is added. The solution is then stirred at115° C. for 4 hours. After cooling, the solution is stirred into water,and the precipitate formed is filtered off and dried at 40° C. The crudeproduct is purified by column chromatography on normal-phase silica gel,giving the product “A1” as colourless powder in a yield of 74%; LC-MS:1.921 min; 448.15 m/e M+H⁺.

¹H-NMR (DMSO-d₆) δ [ppm] 7.79 (dd, 1H; J=8.9 Hz, J=8.9 Hz), 7.30-7.25(m, 2H), 7.19 (s, 1H), 7.14 (t, 1H; J=7.5 Hz), 7.06 (d, 1H; J=8.0 Hz),6.98 (d, 2H, 7.5 Hz), 6.58 (d, 1H; J=1.9 Hz), 6.40 (d, 1H; J=1.9 Hz),5.59 (d, 1H; J=15.8 Hz), 5.36 (d, 1H; J=15.8 Hz), 4.41 (d, 1H; J=14.7Hz), 4.36 (d, 1H; J=14.7 Hz), 3.81 (s, 3H), 1.99 (s, 6H), 1.98 (s, 3H).

EXAMPLE 2

The preparation of2-{2-[1-(2,6-dimethylbenzyl)-1H-benzimidazol-2-yl]-phenoxy}acetamide(“A2”) is carried out as indicated below:

The preparation of the alcohol “10” is carried out analogously toExample 1 described above.

Alcohol “10” (1 eq) is dissolved in acetonitrile, potassium carbonate (3eq) and 2-bromoacetamide (1.1 eq) are added. The solution is stirred atroom temperature for five hours and then heated under reflux for 22hours and left to stand at room temperature for four days. Afterfiltration, the solvent is removed in vacuo. Purification by columnchromatography on normal-phase silica gel gives the product “A2” aspowder in a yield of 8%; LC-MS: 1.787 min; m/e 86.2 (M+H⁺).

¹H-NMR (DMSO-d₆): δ [ppm] 7.81 (d, 1H; J=8.4 Hz), 7.71-7.70 (m, 1H),7.67-7.64 (m, 1H), 7.54 (s, 1H), 7.45 (t, 1H; J=6.6 Hz), 7.41 (s, 1H),7.33 (t, 1H; J=6.6 Hz), 7.22 (t, 1H; J=7.8 Hz), 7.14-7.11 (m, 3H), 6.98(d, 2H, 8.4 Hz), 5.59 (s, 2H), 4.56 (s, 2H), 2.02 (s, 6H).

The following compounds are obtained analogously

LC-MS Rt[min]; m/e No. Name and/or structure [M + H]⁺ “A3”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.412;yl]-3-fluorophenoxy}acetamide 404.8

¹H-NMR (DMSO-d₆): δ [ppm] 7.67 (d, 1H; J = 8.0), 7.56-7.52 (m, 1H), 7.40(s, 2H), 7.20 (t, 1H; J = 8.0), 7.13-7.08 (m, 2H), 6.98-6.91 (m, 5H),5.49 (d, 1H; J = 16.2 Hz), 5.30 (d, 1H; J = 16.2), 4.57 (d, 1H; J = 15.9Hz), 4.48 (d, 1H; J = 15.9 Hz), 2.01 (s, 6H) “A4”2-{2-[1-(2,6-Dimethylbenzyl)-6-fluoro-1H-benz- 1.880;imidazol-2-yl]phenoxy}acetamide 404.1

¹HNMR (DMSO-d₆): δ [ppm] 7.72 (dd, 1H; J = 4.9 Hz, J = 8.6 Hz),7.59-7.56 (m, 2H), 7.50 (s, 1H), 7.36 (s, 1H), 7.18-7.08 (m, 4H), 6.98(d, 2H; J = 7.6 Hz), 6.63 (d, 1H; J = 9.6 Hz), 5.47 (s, 2H), 4.54 (s,2H), 2.01 (s, 6H) “A5” 2-{2-[1-(2,6-Dimethylbenzyl)-5,6-difluoro-1H-1.731; benzimidazol-2-yl]phenoxy}acetamide 422.1 ¹H-NMR (DMSO-d₆): δ[ppm] 7.70 (dd, 1H; J = 7.6 Hz, J = 10.6 Hz), 7.56-7.48 (m, 3H), 7.34(s, 1H), 7.15-7.07 (m, 3H), 6.99 (d, 2H; J = 7.6 Hz), 6.67 (dd, 1H; J =7.4 Hz, J = 11.1 Hz), 5.42 (s, 2H), 4.55 (s, 2H), 1.99 (s, 6H) “A6”2-{2-[6-Fluoro-1-(2,4,6-trimethylbenzyl)-1H- 1.593;benzimidazol-2-yl]phenoxy}acetamide 418.1 ¹H-NMR (DMSO-d₆): δ [ppm] 7.74(dd, 1H; J = 4.7 Hz, J = 8.9 Hz), 7.62-7.56 (m, 2H), 7.51 (s, 1H), 7.38(s, 1H), 7.18 (t, 2H; J = 7.5 Hz), 7.12 (d, 1H; J = 8.8 Hz), 6.82 (s,2H), 6.66 (d, 1H; J = 8.8 Hz), 5.43 (s, 2H), 4.56 (s, 2H), 2.21 (s, 3H),1.98 (s, 6H) “A7” 2-{2-[1-(2-Methylbenzyl)-1H-benzimidazol-2-yl]- 1.213;phenoxy}acetamide 372.4 “A8”2-[2-(1-Benzyl-1H-benzimidazol-2-yl)phenoxy]- 1.654; acetamide 358.2“A9” 2-{2-[1-(2,6-Difluorobenzyl)-1H-benzimidazol-2- 1.624yl]phenoxy}acetamide 394.2 “A10”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.396yl]-6-fluorophenoxy}acetamide 404.8 “A11”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.347yl]-6-methoxyphenoxy}acetamide 416.7 “A12”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.336yl]-6-methylphenoxy}acetamide 400.8 “A13”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.307yl]-5-methoxyphenoxy}acetamide 416.7 “A14”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.307yl]-5-methylphenoxy}acetamide 416.7 “A15”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.324yl]-3-methoxyphenoxy}acetamide 416.7 “A16”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.252yl]pyridin-3-yloxy}acetamide 387.7

“A17” 2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.266yl]-5-fluorophenoxy}acetamide 404.8 “A18”2-{2-[5-Chloro-1-(2,6-dichlorobenzyl)-1H-benz- 1.668imidazol-2-yl]phenoxy}acetamide 461.6 “A19”2-{2-[1-(2,6-Dichlorobenzyl)-5-fluoro-1H-benz- 1.465imidazol-2-yl]phenoxy}acetamide 445.5 “A20”2-{2-[1-(2-Chloro-6-fluorobenzyl)-1H-benzimida- 1.144zol-2-yl]phenoxy}acetamide 410.5 “A21”2-{2-[7-Chloro-1-(2,6-dichlorobenzyl)-1H-benz- 1.811imidazol-2-yl]phenoxy}acetamide 461.6 “A22”2-{2-[1-(2-Chloro-6-methylbenzyl)-1H- 2.001benzimidazol-2-yl]phenoxy}acetamide 406.5 “A23”2-{2-[7-Bromo-1-(2,6-dimethylbenzyl)-1H-benz- 1.312imidazol-2-yl]phenoxy}acetamide 465.6 “A24”2-{2-[7-Chloro-1-(2,6-dimethylbenzyl)-1H-benz- 1.264imidazol-2-yl]phenoxy}acetamide 420.6 “A25”2-{2-[1-(2,6-Dimethylbenzoyl)-1H-benzimidazol- 1.6612-yl]phenoxy}acetamide 400.8

“A26” 3-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.714yl]phenoxy}pyrrolidin-2-one 412.7

“A27” 2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2- 1.646yl]phenoxy}-3-hydroxypropionamide 416.7

“A28” 2-{2-[1-(2,6-Dimethylbenzyl)-5,6-difluoro-1H- 1.77benzimidazol-2-yl]-5-methoxy-3-methyl- 466.1 phenoxy}acetamide “A29”2-{2-[1-(2,6-Dimethylbenzyl)-6,7-difluoro-1H- 1.844benzimidazol-2-yl]phenoxy}acetamide 422.1 “A30”2-{2-[1-(2,6-Dimethylbenzyl)-6,7-difluoro-1H- 1.907benzimidazol-2-yl]-5-methoxy-3-methyl- 466.1 phenoxy}acetamide

EXAMPLE 3

The preparation of(5-{2-[1-(2,6-dimethylbenzyl)-1H-benzimidazol-2-yl]-phenyl}-1,3,4-oxadiazol-2-yl)methylamine(“A31”) is carried out as indicated below

a) A mixture of 430 mg (1.7 mmol) of methyl2-(1H-benzimidazol-2-yl)benzoate (Paulder et. al., J. Org. Chem.,(1969), 34(7) 2130-40), 266.3 mg (1.7 mmol) of 2,6-dimethylbenzylchloride, 235 mg (1.7 mmol) of potassium carbonate and 28 mg ofpotassium iodide in 5 ml of dimethylformamide is stirred at roomtemperature for 48 hours. 20 ml of water are subsequently added to thereaction mixture, the deposited precipitate is separated off, washedtwice with 10 ml of water and dried in air. The methyl2-[1-(2,6-dimethylbenzyl)-1H-benzimidazol-2-yl]benzoate (MS: M+H=371)obtained in this way is then dissolved in a mixture of 4 ml oftetrahydrofuran, 6 ml of methanol and 2 ml of water, 100 mg of lithiumhydroxide are added, and the solution is stirred at room temperature for12 hours. The reaction solution is subsequently evaporated in vacuo, theresidue is dissolved in 5 ml of water, the solution is acidified using 1N hydrochloric acid and extracted three times with 10 ml of ethylacetate each time. Drying of the combined organic extracts over sodiumsulfate and removal of the solvent in vacuo gives 460 mg 480 mg (75%) ofmethyl 2-[1-(2,6-dimethylbenzyl)-1H-benzimidazol-2-yl]benzoate as yellowresin. MS: M+H=357.

b) A mixture of 0.46 g (1.3 mmol) of2-[1-(2,6-dimethylbenzyl)-1H-benzimidazol-2-yl]benzoic acid, 154 mg (1.4mmol) of 4-methylthiosemicarbazide, 300 mg (1.55 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 392 mg(1.68 mmol) of 1-hydroxybenzotriazole and 390 mg (3.87 mmol) of4-methylmorpholine in 10 ml of dimethylformamide is stirred at roomtemperature for 12 hours, and 50 ml of water are subsequently added. Thedeposited precipitate is separated off, washed twice with 10 ml of waterand dried to constant weight at 50° C. in vacuo, giving 436 mg (88%) of1-[2-[1-(2,6-dimethylbenzyl)-1H-benzimidazol-2-yl]-benzoyl]-4-methylthiosemicarbazideas white powder. MS: M+H=444.

c) A solution of 436 mg (0.98 mmol) of the compound from step b) and344.6 mg (1.08 mmol) of mercury(II) acetate is stirred at roomtemperature for 12 hours and subsequently filtered through kieselguhr.The filtrate is evaporated to dryness, and the residue is purified bycolumn chromatography (silica gel: ethyl acetate/methanol 9/1), giving232 mg (57.6%) of “A31” as white powder; MS: M+H: 410; ¹H-NMR (d₆-DMSO):8.1 ppm (m, 1H); 7.93 ppm (m, 1H); 7.84 ppm (d, 1H); 7.80 ppm (d, 1H);7.22-6.65 ppm (m, 4H); 6.99 ppm (t, 1H); 6.73 ppm (d, 2H).

Pharmacological Data Affinity to Receptors

TABLE 1 Compound No. SGLT₁-IC₅₀ SGLT₂-IC₅₀ “A1” C A “A2” C A “A3” A “A4”C A “A5” C A “A6” C C “A7” C B “A8” C C “A9” C B “A10” C A “A11” B “A12”C B “A13” C B “A14” C A “A15” C A “A16” C “A17” C A “A18” C C “A19” C B“A20” C B “A21” C B “A22” C B “A23” C C “A24” B A “A25” C C “A26” C B“A27” C C “A28” C B “A29” C B “A30” B A “A31” A IC₅₀: 10 nM-1 μM = A 1μM-10 μM = B >10 μM = C

The following examples relate to pharmaceutical compositions:

EXAMPLE A Injection vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which R¹, R², R³, R⁴ each, independently of one another, denote H, Aor Hal, R¹, R⁶, R⁷, R⁸ each, independently of one another, denote H, A,Hal, OH or OA, where R⁸ is absent if Q=N, R⁹, R¹⁰, R¹¹, R¹², R¹³ each,independently of one another, denote H, A or Hal, where one of theradicals R⁹, R¹⁰, R¹¹, R¹² or R¹³ is ≠H, R denotes CO—NR¹⁸R¹⁹ or Het, Qdenotes N or C, X denotes O or NR¹⁴R¹⁵, W denotes (CR¹⁴R¹⁵)_(m), CO,NR¹⁴R¹⁵, S(O)_(n) or is absent, Z denotes (CR²⁰R²¹)_(m), R¹⁴, R¹⁵ each,independently of one another, denote H or A, R¹⁶, R¹⁷ each,independently of one another, denote H or A, R¹⁸, R¹⁹ each,independently of one another, denote H or A, R²⁰ denotes H or A, R²¹denotes H, A or CH₂OH, R¹⁸ and R²¹ together also denote (CR¹⁶R¹⁷)_(p),Het denotes a mono- or bicyclic saturated, unsaturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms, which may beunsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NR¹⁴R¹⁵and/or ═O (carbonyl oxygen), A denotes unbranched or branched alkylhaving 1-10 C atoms, in which 1-7H atoms may be replaced by F, Haldenotes F, Cl, Br or I, m denotes 0, 1, 2, 3 or 4, n denotes 0, 1 or 2,p denotes 1, 2 or 3, and pharmaceutically usable derivatives, solvates,salts and stereoisomers thereof, including mixtures thereof in allratios.
 2. Compounds according to claim 1 in which A denotes unbranchedor branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms, in which 1-5H atomsmay be replaced by F, and pharmaceutically usable derivatives, solvates,salts and stereoisomers thereof, including mixtures thereof in allratios.
 3. Compounds according to claim 1 in which R¹, R², R³, R⁴ each,independently of one another, denote H, CH₃, F or Cl, andpharmaceutically usable derivatives, solvates, salts and stereoisomersthereof, including mixtures thereof in all ratios.
 4. Compoundsaccording to claim 1 in which R⁵, R⁶, R⁷, R⁸ each, independently of oneanother, denote H, CH₃, Hal or OCH₃, where R⁸ is absent if Q=N, andpharmaceutically usable derivatives, solvates, salts and stereoisomersthereof, including mixtures thereof in all ratios.
 5. Compoundsaccording to claim 1 in which R⁹, R¹⁰, R¹¹, R¹², R¹³ each, independentlyof one another, denote H, CH₃, F or Cl, where one of the radicals R⁹,R¹⁰, R¹¹, R¹² or R¹³ is ≠H, and pharmaceutically usable derivatives,solvates, salts and stereoisomers thereof, including mixtures thereof inall ratios.
 6. Compounds according to claim 1 in which R⁹, R¹³ each,independently of one another, denote CH₃, F or Cl, R¹¹ denotes H or CH₃,R¹⁰, R¹² denote H, and pharmaceutically usable derivatives, solvates,salts and stereoisomers thereof, including mixtures thereof in allratios.
 7. Compounds according to claim 1 in which X denotes O, andpharmaceutically usable derivatives, solvates, salts and stereoisomersthereof, including mixtures thereof in all ratios.
 8. Compoundsaccording to claim 1 in which W denotes (CR¹⁴R¹⁵)_(m) or CO, andpharmaceutically usable derivatives, solvates, salts and stereoisomersthereof, including mixtures thereof in all ratios.
 9. Compoundsaccording to claim 1 in which R¹⁴, R¹⁵ denote H, and pharmaceuticallyusable derivatives, solvates, salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 10. Compounds according to claim 1 inwhich R¹⁶, R¹⁷ denote H, and pharmaceutically usable derivatives,solvates, salts and stereoisomers thereof, including mixtures thereof inall ratios.
 11. Compounds according to claim 1 in which R¹⁸, R¹⁹ denoteH, and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, including mixtures thereof in all ratios. 12.Compounds according to claim 1 in which R²⁰ denotes H, R²¹ denotes H orCH₂OH, and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, including mixtures thereof in all ratios. 13.Compounds according to claim 1 in which Het denotes a mono- or bicyclicsaturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, which may be mono- or disubstituted by NR¹⁴R¹⁵ and/or ═O(carbonyl oxygen), and pharmaceutically usable derivatives, solvates,salts and stereoisomers thereof, including mixtures thereof in allratios.
 14. Compounds according to claim 1 in which Het denotespiperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl,indolyl, benzo-1,3-dioxolyl, indazolyl or benzo-2,1,3-thiadiazolyl, eachof which is unsubstituted or mono- or disubstituted by NR¹⁴R¹⁵ and/or ═O(carbonyl oxygen), and pharmaceutically usable derivatives, solvates,salts and stereoisomers thereof, including mixtures thereof in allratios.
 15. Compounds according to claim 1 in which A denotes unbranchedor branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms, in which 1-5H atomsmay be replaced by F, Het denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,benzo-1,3-dioxolyl, indazolyl or benzo-2,1,3-thiadiazolyl, each of whichis unsubstituted or mono- or disubstituted by NR¹⁴R¹⁵ and/or ═O(carbonyl oxygen), R¹, R², R³, R⁴ each, independently of one another,denote H, CH₃, F or Cl, R⁵, R⁶, R⁷, R⁸ each, independently of oneanother, denote H, CH₃, Hal or OCH₃, where R⁸ is absent if Q=N, R⁹, R¹³each, independently of one another, denote CH₃, F or Cl, R denotesCO—NR¹⁸R¹⁹ or Het, R¹¹ denotes H or CH₃, R¹⁰, R¹² denote H, Q denotes Nor C, X denotes O, W denotes (CR¹⁴R¹⁵)_(m) or CO, Z denotes(CR²⁰R²¹)_(m), R¹⁴, R¹⁵ denote H, R¹⁶, R¹⁷ denote H, R¹⁸, R¹⁹ denote H,R²⁰ denotes H, R²¹ denotes H or CH₂OH, R¹⁸ and R²¹ together also denote(CR¹⁶R¹⁷)_(p), m denotes 0, 1 or 2, p denotes 1 or 2, andpharmaceutically usable derivatives, solvates, salts and stereoisomersthereof, including mixtures thereof in all ratios.
 16. Compoundsaccording to claim 1 selected from the group No. Name “A1”2-{2-[1-(2,6-Dimethylbenzyl)-6-fluoro-1H-benzimidazol-2-yl]-5-methoxy-3-methylphenoxy}acetamide “A2”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]- phenoxy}acetamide“A3” 2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-3-fluorophenoxy}acetamide

“A4” 2-{2-[1-(2,6-Dimethylbenzyl)-6-fluoro-1H-benzimidazol-2-yl]phenoxy}acetamide

“A5” 2-{2-[1-(2,6-Dimethylbenzyl)-5,6-difluoro-1H-benzimidazol-2-yl]phenoxy}acetamide “A6”2-{2-[6-Fluoro-1-(2,4,6-trimethylbenzyl)-1H-benzimidazol-2-yl]phenoxy}acetamide “A7”2-{2-[1-(2-Methylbenzyl)-1H-benzimidazol-2-yl]phenoxy}- acetamide “A8”2-[2-(1-Benzyl-1H-benzimidazol-2-yl)phenoxy]acetamide “A9”2-{2-[1-(2,6-Difluorobenzyl)-1H-benzimidazol-2-yl]- phenoxy}acetamide“A10” 2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-6-fluorophenoxy}acetamide “A11”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-6-methoxyphenoxy}acetamide “A12”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-6-methylphenoxy}acetamide “A13”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-5-methoxyphenoxy}acetamide “A14”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-5-methylphenoxy}acetamide “A15”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-3-methoxyphenoxy}acetamide “A16”2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]pyridin-3-yloxy}acetamide

“A17” 2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-5-fluorophenoxy}acetamide “A18”2-{2-[5-Chloro-1-(2,6-dichlorobenzyl)-1H-benzimidazol-2-yl]phenoxy}acetamide “A19”2-{2-[1-(2,6-Dichlorobenzyl)-5-fluoro-1H-benzimidazol-2-yl]phenoxy}acetamide “A20”2-{2-[1-(2-Chloro-6-fluorobenzyl)-1H-benzimidazol-2-yl]-phenoxy}acetamide “A21”2-{2-[7-Chloro-1-(2,6-dichlorobenzyl)-1H-benzimidazol-2-yl]phenoxy}acetamide “A22”2-{2-[1-(2-Chloro-6-methylbenzyl)-1H-benzimidazol-2-yl]-phenoxy}acetamide “A23”2-{2-[7-Bromo-1-(2,6-dimethylbenzyl)-1H-benzimidazol-2-yl]phenoxy}acetamide “A24”2-{2-[7-Chloro-1-(2,6-dimethylbenzyl)-1H-benzimidazol-2-yl]phenoxy}acetamide “A25”2-{2-[1-(2,6-Dimethylbenzoyl)-1H-benzimidazol-2-yl]- phenoxy}acetamide

“A26” 3-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-phenoxy}pyrrolidin-2-one

“A27” 2-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-phenoxy}-3-hydroxypropionamide

“A28” 2-{2-[1-(2,6-Dimethylbenzyl)-5,6-difluoro-1H-benzimidazol-2-yl]-5-methoxy-3-methylphenoxy}acetamide “A29”2-{2-[1-(2,6-Dimethylbenzyl)-6,7-difluoro-1H-benzimidazol-2-yl]phenoxy}acetamide “A30”2-{2-[1-(2,6-Dimethylbenzyl)-6,7-difluoro-1H-benzimidazol-2-yl]-5-methoxy-3-methylphenoxy}acetamide “A31”(5-{2-[1-(2,6-Dimethylbenzyl)-1H-benzimidazol-2-yl]-phenyl}-1,3,4-oxadiazol-2-yl)methylamine

and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, including mixtures thereof in all ratios. 17.Process for the preparation of compounds of the formula I according toclaim 1 and pharmaceutically usable derivatives, solvates, salts andstereoisomers thereof, characterised in that a) a compound of theformula II

in which R¹, R², R³, R⁴, R⁹, R¹⁰, R¹¹, R¹², R¹³ and W have the meaningsindicated in claim 1, is reacted with a compound of the formula III

in which R⁵, R⁶, R⁷, R⁸, R, Q, W and Z have the meanings indicated inclaim 1, or b) a compound of the formula IV

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, Q and Whave the meanings indicated in patent claim 1, is reacted with acompound of the formula VL-Z-R  V in which Z and R have the meanings indicated in patent claim 1,and L denotes Cl, Br, I or a free or reactively functionally modified OHgroup, and/or a base or acid of the formula I is converted into one ofits salts.
 18. Medicaments comprising at least one compound of theformula I according to claim 1 and/or pharmaceutically usablederivatives, solvates, salts and stereoisomers thereof, includingmixtures thereof in all ratios, and optionally excipients and/oradjuvants.
 19. Medicaments comprising at least one compound of theformula I according to claim 1 and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and at least one further medicament activeingredient.
 20. A method for the treatment of type 1 and type 2 diabetescomprising administering an effective amount of a compound of claim 1 toa subject in need thereof.
 21. A method for lowering blood sugarcomprising administering an effective amount of a compound of claim 1 toa subject in need thereof.
 22. (canceled)
 23. Set (kit) consisting ofseparate packs of (a) an effective amount of a compound of the formula Iaccording to claim 1 and/or pharmaceutically usable derivatives,solvates, salts and stereoisomers thereof, including mixtures thereof inall ratios, and (b) an effective amount of a further medicament activeingredient.
 24. (canceled)